ArticleeLife2014
p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition.
Article in eLife, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 137 papers.
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Who cites it
137 citing papers in PubMed, 217 citations in OpenAlex.
- Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.GeroScience · 2026Article
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.PLoS genetics · 2026Article
- Subcellular localization as a driver of protein function.Nature reviews. Molecular cell biology · 2026Review
- Proteasome inhibition enhances lysosome-mediated targeted protein degradation.Cell death & disease · 2026Article
- Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.Frontiers in cellular neuroscience · 2026Review
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.bioRxiv : the preprint server for biology · 2025Article
- Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease.Brain : a journal of neurology · 2025Article
- How multispecific molecules are transforming pharmacotherapy.Nature reviews. Drug discovery · 2025Review
- Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.Molecular biology of the cell · 2025Article
- Harnessing mitochondrial biogenesis to combat acute kidney injury: Current insights and futuredirections.Genes & diseases · 2025Review
- Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.PLoS genetics · 2025Article
- Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.PLoS genetics · 2025Article
- NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.Frontiers in molecular neuroscience · 2025Review
- Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories.Cell stress · 2025Review
- Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Ferroptosis regulation by Cap'n'collar family transcription factors.The Journal of biological chemistry · 2024Review
- Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, against MASLD Progression.International journal of molecular sciences · 2024Article
- Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans.PLoS biology · 2024Article
- Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer.Antioxidants (Basel, Switzerland) · 2024Review
77 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery (i.e., 'bounce-back') of proteasome activity. We previously demonstrated that the transcription factor Nrf1/NFE2L1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded promptly by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol. DOI: http://dx.doi.org/10.7554/eLife.01856.001.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.